The present invention relates to methods for moving biological cells, in particular for transfer of at least one biological cell carrying out a natural cell locomotion between a carrier and a probe, such as e.g. cell transfer method for removing or for introducing biological cells or cell groups into or out of cell material, manipulation and/or examination devices, which are adapted for carrying out such methods, in particular probes for transfer of at least one biological cell from or to a carrier, cell manipulators, which have at least one such manipulation and/or examination device, and applications of the abovementioned methods.
In medicine, biotechnology and biochemistry there are countless methods in which biological cells are examined or processed or used for examination or processing (modifying) biological material. For example cells are removed for medical cell therapy from an animal or human proband, treated, collected, sorted and/or cultivated outside the proband body in order to then recycle specific cells or cell groups in the probands. Specific advantages are expected from medical cell therapy with stem cells, since they possess the ability of differentiating almost all cell types of the body and therefore represent candidates for individual cell therapies and for in-vitro regeneration of tissue. Today it is assumed that under appropriate conditions adult or embryonic stem cells are suited to virtually all cell output of the body and therefore also for developing or regenerating different tissues. There is therefore strong interest in secure and reproducible handling of biological cells.
Essential tasks with examination or manipulation of biological cells, in particular in connection with medical cell therapy and tissue engineering, comprise the fact that individual, previously selected cells or cell groups can be added or removed, or defined measurements can be taken at predetermined locations, for example in the tissue or in a cell bond with precision in the μm range. To date e.g. stem cells are transmitted into target tissue using a syringe. These tasks must be solvable without impairment or damage to the cells or the tissues, and with a high degree of reproducibility, controllability and precision. These requirements however have not been satisfactorily answered to date.
It is known from practice that contradictory results have been achieved in animal testing despite similarly carried out methods, e.g. by injection of cells into diseased tissue. It was found that the positive course of tissue regeneration depends sensitively on the procedural conditions, in particular on the type of injection, the number of introduced cells or substances and the injection tool used. In numerous experiments it was not the desired regeneration or new development of a cell or tissue type which occurred, but for example induction of tumours. It is assumed that the induction of tumours as uncontrolled cell increase of stem cells is promoted through physical, chemical or outside mechanical influences at the injection site. These influences cannot be adjusted or at least acquired reproducibly with conventional injection techniques.
Stress-free and selective removal of adherent growing cells from in vitro cultures causes the following problems. First, mechanical scraping of the desired cells is possible. But at the same time there is the abovementioned risk of damage. Alternatively, detachment can be provided by trypsination, which represents a strong, unphysiological biochemical intervention in the cell culture, with the result that the adhesion proteins of the detached cells must be newly expressed. Also, trypsination constitutes a problem for selectivity of the cell removal. Selected cells can be rediscovered after trypsination only and removed individually from the culture with difficulty.
These problems in the cell therapy and results from tissue engineering, to date partially unsatisfying, currently constitute the most significant limitations and delays with a wide application of these methods in biotechnology and medicine.
The object of the invention is to provide improved methods for movement of biological cells relative to a foreign body, such as for example a carrier and a probe, with which the disadvantages of conventional methods are overcome and which enable in particular a smooth cell transfer between the carrier and the probe, whereby mechanical or biochemical influences on the transferred cell or on cells, present if necessary on the carrier or the probe, are to be minimised. In particular unphysiological interventions, such as trypsination, should be avoided in the cell material. The object of the invention is also to provide improved manipulation and/or examination devices (probes) for performing such methods, and cell manipulators, which are equipped with at least one such probe, with which the disadvantages of conventional injection or biopsy instruments can be overcome. The object of the invention is also to provide novel applications of probes for transfer of cells.